Episodic memory is characterized by our ability to remember the spatial and temporal context in which events occur. There is substantial evidence that the hippocampal neuronal activity reflects a representation of space but, until recently, little was known about whether or how the hippocampal neurons encode time. However, recent studies by us have shown that hippocampal neuronal activity provides a temporal context signal that contributes to memory. In addition there is now evidence that hippocampal neurons - called time cells - fire during particular moments in a temporally extended experience, similar to hippocampal place cells that fire associated with particular locations in a spatially extended environment. The proposed studies will explore the nature of temporal representation by the hippocampal system and prefrontal cortex. We will test the hypothesis that key properties of time cells are analogous to those of place cells. By simultaneous recordings in multiple areas, we will also test the hypothesis that time cells are paralleled by a periodic representation of time in the medial entorhinal cortex and prefrontal cortex representation that disambiguates overlapping experiences. Using both muscimol and optical silencing methods, we will further test the hypothesis that temporal coding in the hippocampus depends on the medial entorhinal cortex, and that the ability of hippocampal time cells to disambiguate overlapping experiences depends on the prefrontal cortex. These studies will challenge the prevalent view that the hippocampal system is dedicated to spatial navigation and advance our understanding of how this system represents events in their spatiotemporal context. PUBLIC HEALTH RELEVANCE: Our understanding of cognitive disorders, and the eventual development of treatments, depends crucially upon an understanding of the cognitive and neural mechanisms that underlie normal cognition;for example, abnormal thought patterns in schizophrenia, as well as other cognitive disorders, reflects an underlying disorganization of the neural machinery that stores and retrieves memories of our everyday experiences. The proposed work will pioneer a new understanding about how memories are represented in neural circuitry and about how neural representations are organized to guide our retrieval of memories in daily life. Because the hippocampus and adjacent cortical areas are compromised in multiple major mental disorders, an understanding the functional circuitry of these areas is particularly important.